The incidence of asthma and respiratory allergy is increasing in epidemic proportion throughout the world. It is one of the most critical, torturous diseases, which is threatening human civilization. Current studies have shown that the loss due to asthma and other respiratory disorders is more that 30-34% of the total man-days. Even today there is no clear curative therapy for the disease. Moreover, currently available remedial drugs i.e., bronchodilators and steroids, are with undetermined responsiveness, and hazardous to health, with severe side effects.
The basic aspect of the disease is the blockage of air passage of the lungs, usually occurring due to the formation of leukotriene (LK) molecules from arachidonic acid (AA). LK acts on the cell surface receptor producing cellular oedema, swelling and mucus secretion. All these together cause constriction of air-passage resulting in the torturous and fatal disease-Asthma. The response to the three major classes of asthma therapy, beta-agonists, leukotriene antagonists, and inhaled corticosteroids, demonstrates wide inter-individual variability, with a significant number of non-responders.
Recent studies suggest that interleukin-4 (IL-4) mediates important proinflammatory functions in asthma including induction of IgE isotype switch and promotion of eosinophil transmigration across endothelium, mucous secretion and differentiation of T helper type 2 (Th2 type) lymphocytes. Therefore, IL-4 antagonists may have potential as therapeutic agent in asthma (Respiratory Research 2001, 2, 66-70).
The presence of increased numbers of airway eosinophils in asthmatic patients suggest that this cell plays a key role in the pathogenesis of asthma (Am. J. Respir. Crit. Care Med. 1999, 160, 1001-1008). Eosinophils produce proinflammatory mediators. IL-5 promotes eosinophil differentiation and activation, as well as trafficking into the lungs (Ann. Rev. Immunol. 2006, 24, 147-174). Thus, IL-5 antagonists may also have potential for the treatment of asthma.
Hydroxychavicol is known to induce cell cycle arrest and apoptosis in oral KB carcinoma cell line (Cell. Mol. Life Sci., 2004, 61, 83-96) and in hepatocarcinoma cells (Cancer lett., 2000, 155, 29-35). Hydroxychavicol has anti-oxidative property inducing cell-cycle arrest and apoptosis of oral KB carcinoma cells (British Journal of Pharmacology, 2002, 135, 619-630), anti-mutagenic property against tobacco-specific carcinogens (Mutat. Res., 1989, 210, 249 253), as well as chemopreventive activity against benzo[a]pyrene induced for stomach tumors in mice (J. Ethnopharmacol., 1991, 34, 207-213). Conflicting literature exists on the effect of hydroxychavicol on cycloxygenase 2: while one report suggested enhancement of expression (J. Oral Pathol. Med., 2003, 32, 522-529), another report suggested hydroxychavicol-mediated inhibition of platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization (British Journal of Pharmacology, 2007, 152, 73-82). Hydroxychavicol is a potent COX-1/COX-2 inhibitor and could be potentially used in prevention or treatment of cardiovascular disease through its anti-inflammatory effect (British Journal of Pharmacology, 2007, 152, 73-82). The chemopreventive efficacy of betel leaf extract and its constituents, including hydroxychavicol on 7,12-dimethylbenz(a)anthracene induced skin tumors in mouse, has been reported (Indian Journal of Experimental Biology, 1991, 29, 346-351). The anti-mutagenic and anti-carcinogenic properties of hydroxychavicol and eugenol have been reported (Mutagenesis, 1989, 4, 200-204). Another recent report suggested that allylpyrocatechol (hydroxychavicol) inhibited NF-κB pathway in lipopolysaccharide (LPS)-induced macrophages leading to suppression of iNOS, interleukin-12 and TNF-α (International Immunopharmacology, 2008, 8, 1264-1271).
The present invention relates to inhibition of IL-4 and IL-5 by hydroxychavicol (purified from natural sources or prepared synthetically) and its analogues and shows anti-asthmatic efficacy in vivo in mouse model.